Type 1 diabetes mellitus occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of the pancreatic beta-cells mediated by autoreactive T-cells. Our long-range goals are to understand the natural history of Type 1 diabetes and to participate in the evaluation of potential new approaches to prevent or ameliorate this disease. The objectives of this application are threefold: 1) to complete the ongoing Diabetes Prevention Trial-Type 1 (DPT-1), 2) to be involved in the design and implementation of new intervention strategies and, 3) to propose a novel intervention strategy, to test the effects of an altered peptide ligand (APL), NBI-6024 (Neurocrine Biosciences), in individuals at risk for clinical Type 1 diabetes. The central hypothesis of this proposed study is that administration of this APL, containing two natural L-amino acid substitutions from the insulin B-chain (9-23) region, will temper the destructive autoimmune process leading to Type 1 diabetes, preserving beta-cells and their insulin-secreting capacity. The rationale for this study is that, if treatment with this APL is safe and effective at stopping or slowing disease progression in a population at defined risk, it could be tested at an earlier stage of diabetes development, in those with less well-defined risk, and possibly result in large-scale prevention. We will test the central hypothesis of our proposed study and accomplish the objectives as a TriaINet Clinical Center by pursuing the following three Specific Aims: 1. Complete the DPT-1 protocols and achieve their objectives, 2. Establish a network of collaborating investigators to participate in the design and conduct of future studies to evaluate new approaches to prevent or ameliorate Type 1 diabetes, 3. Evaluate the effects of intervention with an APL on progression to clinical diabetes in individuals at risk for Type 1 diabetes. It is our expectation that the DPT-1 protocols will be successfully completed, and that insulin administration will alter the destructive immune response in the beta-cells, and attenuate beta-cell autoimmunity, thereby preventing or delaying the development of Type 1 diabetes. The data collected will also better characterize the natural history of Type 1 diabetes disease development. It is also our expectation, based on our Clinical Center performance in the DPT-1, and on the expertise of our investigators, that our contribution to the Diabetes TriaINet will help to ensure its successful implementation and facilitate its functioning as envisioned in future intervention trials. Additionally, we will test the hypothesis that our innovative intervention plan based on the administration of APL NBI-6024 will prevent or reduce disease progression. If not prevented, a treatment effect that preserves beta-cell function in those who do develop diabetes will provide an important clinical benefit.